Anaplastic lymphoma kinase (ALK) is a receptor tyrosine kinase in the insulin receptor superfamily. ALK plays an important role in the development of the brain and exerts its effects on specific neurons in the nervous system. Aberrant expression and hyperactivation of ALK due to translocations or point mutations have been shown to be oncogenic in a large variety of cancers, e.g., inflammatory myofibroblastic tumors, diffuse large B cell lymphoma, squamous cell carcinoma, and non-small-cell lung carcinoma. Lung cancers with ALK rearrangements are highly sensitive to ALK tyrosine kinase inhibition, underscoring that such cancers are addicted to ALK kinase activity. ALK is therefore widely recognized as an attractive target for the design and development of diagnostic or therapeutic agents. For example, the ALK inhibitor, Crizotinib was approved by the FDA to treat patients with advanced NSCLC harboring ALK rearrangements. However, despite a high response rate in ALK rearranged NSCLC, most patients develop resistance to Crizotinib after 1 year of treatment. In particular, the central nervous system (CNS) is one of the most common sites of relapse.
Studies of lung cancers harboring ALK rearrangements with acquired resistance to Crizotinib have identified ALK fusion gene amplification and secondary ALK kinase domain mutations. The most frequently identified secondary mutations are L1196M (gatekeeper mutation), G1269A, 1151T-ins, L1152R, C1156Y, G1202R, F1174L, and S1206. Several second generation ALK inhibitors have been developed in an attempt to overcome resistance due to these secondary mutants, however, the G1202R mutant confers resistance to all clinical stage ALK inhibitors. At present, suitable compounds targeting G1202R mutant ALK are not available.
Serine-arginine protein kinases (SRPKs) constitute a relatively novel subfamily of serine-threonine kinases (e.g., SRPK1 and SRPK2) that specifically phosphorylate serine residues residing in serine-arginine/arginine-serine dipeptide motifs. Serine-rich protein kinase-1 (SRPK1) has been identified as a regulator of pro-angiogenic vascular endothelial growth factor (VEGF) splicing by phosphorylating serine-rich splicing factor-1 (SRSF1), which binds to VEGF pre-mRNA. VEGF is alternatively spliced to form a family of multiple isoforms, each having different biological properties and activities. Most cells commonly express isoforms VEGF121, VEGF165, and VEGF189, whereas VEGF145 and VEGF206 are comparatively rare. The majority of VEGF isoforms contain exons 1-5 and varying portions of exons 6 and 7. Knockdown of SRPK1 potently reduces VEGF mediated angiogenesis in tumors in vivo, and inhibition of SRPK 1 and 2 decreases angiogenesis in vivo. In addition, it is discovered that inhibition of SRPK1 can switch the splicing isoform pattern for VEGF from 165 (pro-angiogenic) to 165b (anti angiogenic).
Age-related macular degeneration (AMD) is the leading cause of blindness in people over 50 years of age. Choroidal neovascularization (CNV) is the abnormal growth of new vessels from the choroid into the retinal pigmented epithelium (RPE), and is thought to lead to visual loss due to the leakage of blood and serous fluid beneath the RPE. VEGF, a key factor in angiogenesis and vascular leakage is up-regulated during the progression of CNV, and has become a promising therapeutic target for the treatment of eye diseases associated with vascularization, such as AMD.
Thus, there is a need for novel and potent small molecule ALK inhibitors, such as inhibitors with activity against the G1202R mutation, as well as small molecule SRPK inhibitors. The present application addresses the need.